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ABSTRACT
Cutaneous abnormalities in patients with end-stage renal disease (ESRD) receiving hemodialysis or peritoneal dialysis
may demonstrate signs of their underlying condition or
reveal associated disease entities. While a thorough examination of the scalp, skin, mucosa, and nails is integral to establishing a diagnosis, certain conditions will resolve only with
dialysis or improvement of their renal disease and others
may not require or respond to treatment. Half and half nails,
pruritus, xerosis, and cutaneous hyperpigmentation are common manifestations in ESRD. With hemodialysis, uremic
frost is no longer prevalent in ESRD patients and ecchymo-
ses have decreased in incidence. Acquired perforating dermatoses are seen in over one-tenth of hemodialysis patients.
Metastatic calcinosis cutis and calciphylaxis are both rarely
reported, although the latter is seen almost exclusively in the
setting of hemodialysis. Diagnosis of nephrogenic systemic
brosis has historically been challenging; as such, new diagnostic criteria have been proposed. Blood porphyrin proles
are needed to differentiate between porphyria cutanea tarda
and pseudoporphyria. We will review and provide an update
on the aforementioned common cutaneous manifestations of
ESRD in patients receiving dialysis.
Uremic Frost
Uremic frost has become an uncommon cutaneous
presentation of severe renal failure as hemodialysis is
now widely available (1). One study found the prevalence of uremic frost to be 3% in their patient population
(1). Urate crystals are yellowish-white and appear on the
face, neck, and arms, and are due to eccrine deposition
of urea crystals (1). It used to be a common manifestation of chronic renal failure, but its incidence has
decreased due to the widespread use of hemodialysis (1).
White, friable, crystalline structures can be observed.
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Ecchymosis
Ecchymoses in ESRD are not uncommon and can be
detected frequently in the skin and oral mucosa (22).
Although some studies report a lower incidence of
ecchymoses as dialysis has become more widely used
(23), in clinical practice, the incidence of ecchymoses has
appeared to remain constant. An ecchymosis is characterized by a purple skin discoloration due to intradermal
or subcutaneous bleeding, which fades to a yellow-green
color over 12 weeks (Fig. 2). Prolonged bleeding from
venipuncture sites, epistaxis, GI bleeding, or gingival
bleeding may be seen in patients demonstrating ecchymoses (23). An ecchymosis demonstrates extravasated
red blood cells in the dermis or subcutis.
Ecchymosis and the other bleeding abnormalities
are often seen with ESRD due to preexisting global
platelet dysfunction. To form a functioning clot,
platelets must aggregate at the endothelium and
release ADP and serotonin, which recruit more platelets to the damaged vessel wall (23). In ESRD, the
ability of platelets to store ADP and serotonin factors
is diminished. Therefore, platelets are less able to
aggregate at the endothelium leading to bleeding
disorders. Additionally, thrombocytopenia may be
seen in advanced renal disease (24). The differential
diagnosis includes trauma, inherited coagulation disorders such as hemophilia A or B, anticoagulation
therapy, solar purpura, immune thrombocytopenia,
and thrombotic thrombocytopenic purpura. A history
of trauma will help rule out traumatic ecchymoses or
solar purpura in addition to appropriate laboratory
tests to evaluate for any coagulopathies.
Urea, creatinine, phenol, phenolic acid, and guanidinosuccinic acid (GSA) are elevated in ESRD, which
contribute to platelet dysfunction (23). However,
serum levels of these toxins do not correlate with
bleeding time and thus dialysis is not a denitive
treatment for this disorder as the risk for bleeding is
Follicular hyperkeratosis is overproliferation of keratin in the hair follicles. There are many different types of
follicular hyperkeratosis, such as familial, sporadic,
malignancy associated, postinammatory, postirradiation; however, it may be challenging to distinguish
between these types both clinically and histologically
(27). It is also difcult to attribute one histological form
of hyperkeratosis to ESRD. Non-neoplastic follicular
hyperkeratosis is often associated with renal failure (27).
The spicules composing hyperkeratosis have digitatelike projections and can appear across the face, neck, and
chest. Histologically, spicules show abnormal keratinization with columns of orthokeratosis with focal and
admixed serum and inammatory cells. Eosinophilic
material deposited in stratum corneum, spinosa, and
granulosa is visible with H&E stain. IgG kappa is found
in epidermis and upper dermis and in the serum (27). The
etiology of follicular hyperkeratosis is unknown (28).
Follicular hyperkeratosis is nonspecic for ESRD;
therefore, it is important to develop a broad differential
diagnosis in order to rule out any other potential systemic abnormalities. The differential includes malignancy-associated conditions such as multiple myeloma
with amyloidosis, melanoma, familial or sporadic hyperkeratosis, polycystic kidney disease, pellagra, zinc deciency, hyperlipoproteinemia, and postirradiation (27).
Twelve percent ammonium lactate cream or lotion
or urea compounds may improve the follicular
hyperkeratosis.
Acquired Perforating Dermatoses
Acquired perforating dermatoses (APD) are a broad
spectrum of disorders where transepidermal elimination
of material from the dermis is seen with minimal damage
to the surrounding structures. APD is most commonly
seen in patients with end-stage renal disease or diabetes
(29,30). The clinical and histologic features of APD may
resemble any of the four primary perforating skin disorders: elastosis perforans serpiginosa, reactive perforating
collagenosis, perforating folliculitis, or Kyrles disease.
Up to 11% of hemodialysis patients develop APD
(29). In a Turkish study, nearly three-quarters of patients
with APD had CKD, 50% had diabetes, and 9.1% were
renal transplant recipients (30). All of the patients with
renal failure were on dialysis and the disease is suspected
to be linked to the dialysis treatments (30). APD arises in
adults (mean age 48 years), most commonly in the setting of diabetes mellitus or chronic renal failure (30).
APD is characterized by scattered cone-shaped and
plugged hyperkeratotic papules, plaques, and nodules in
areas predisposed to supercial trauma and friction
(e.g., extensors) (29). Lesions may be linearly arranged
secondary to koebnerization (29) (Figs. 3 and 4). Severe
pruritus is frequently reported (29).
Histopathology is required to establish a diagnosis of
APD (31). Skin biopsy reveals an epidermal invagination or dilated hair follicle with a keratotic plug
consisting of keratin, collagen or elastic bers and neutrophils (29,30). The pathophysiology of APD is not well
understood, but may be secondary to poor healing in
diabetes-induced microangiopathy or underlying renal
disease (29). Scratching-induced local trauma or dermal
necrosis, challenged by microvasculopathy, results in
extrustion of dermal material through the epidermis
(32). A foreign body reaction to altered dermal collagen
and calcium salt deposition in certain patients is also
suspected as a possible etiology of APD (32).
Skin biopsy is diagnostic for APD (29). Other
perforating dermatoses should be considered. Prurigo
nodularis, folliculitis, arthropod bites, multiple keratoacanthomas, psoriasis, and lichen planus may clinically
mimic APD and should be excluded (33).
A variety of conventional treatment options have
produced equivocal results in APD. Topical and systemic retinoids, topical corticosteroids and keratolytics,
ultraviolet B phototherapy, psoralen plus ultraviolet A,
allopurinol, cryosurgery, and photodynamic therapy
may be considered in the management of APD (34).
Metastatic Calcinosis Cutis
Metastatic calcinosis cutis (MCC), a subtype of calcinosis cutis, is a rare manifestation of systemic calcinosis where insoluble calcium and phosphate salts are
deposited in the dermis and subcutaneous tissue
(35,36). MCC is a late complication of chronic renal
failure (36). While calcinosis cutis is found in approximately 1% of patients with ESRD on dialysis annually, MCC is rarely reported (37). MCC has been
reported in genders and ages ranging from infants to
the elderly (36). Risk factors for the broader calicinosis
cutis were female gender, low levels of serum albumin,
high serum phosphate or total alkaline phosphatase
levels, and morbid obesity (35). Usually, painless exural inltrating plaques appear at periarticular sites;
the size and number of these calcications correlate
with the degree of hyperphosphatemia (29,35,38).
Unlike calciphylaxis, this benign nodular calcication
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Fig. 10. Porphyria cutanea tarda. Note the white milia and tensa
bulla.
Fig. 9. Porphyria cutanea tarda. Note the milia and large tense
bulla.
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Pseudoporphyria
Conclusions
Pseudoporphyria (PP), also known as bullous dermatosis of ESRD, is a photodermatosis that clinically and
histopathologically resembles porphyria cutanea tarda.
Like PCT, PP is seen in patients with chronic renal failure or undergoing long-term hemodialysis. However,
differentiation between patients with PP and patients
with PCT is possible through their different porphyrin
proles.
PP occurs in about 1.218% of patients with ESRD
on hemodialysis and less frequently in those on peritoneal dialysis (68,69). Development of PP has also been
associated with ultraviolet A (UVA) tanning beds,
psoralen UVA (PUVA), phototherapy with ultraviolet
B (UVB), and medications including diuretics, nonsteroidal antiinammatory drugs (e.g., naproxen), antibiotics, antifungal drugs (e.g., voriconazole), and
retinoids (6974). Recently, reports suggest that
pseudoporphyria can be induced by nasteride and imatinib mesylate (3,44).
PP and PCT both clinically present as skin fragility,
bullae on photo-exposed areas of the skin (especially on
the dorsal portions of forearms and hands), dystrophic
calcication, and milia (75) (Fig. 12). Unlike PCT, however, hypertrichosis and sclerodermoid changes are not
seen in PP (29,74).
Histopathological examination of lesional skin reveals
subepidermal, cell-poor, blister formation with intracorneal hemorrhages and no inammatory inltrate (68).
Mild perivascular lymphocytic inammation can be seen
in some patients, along with sclerosis of collagen (3).
Caterpillar bodies may be seen, mimicking PCT. In both
PP and PCT, direct immunoorescence reveals vascular
and junctional C3 and immunoglobulin deposits, but
direct immunoorescence may be negative (3,68).
Financial Disclosures
None.
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